Sal-like protein 4 (SALL4), a stem cell biomarker in liver... : Hepatology (original) (raw)

Hepatobiliary Malignancies

Oikawa, Tsunekazu1,2; Kamiya, Akihide3,*; Zeniya, Mikio4; Chikada, Hiromi3; Hyuck, Ahn Dong5; Yamazaki, Yuji5; Wauthier, Eliane2; Tajiri, Hisao1; Miller, Lance D.6; Wang, Xin Wei7; Reid, Lola M.2,8,9,**; Nakauchi, Hiromitsu5

1_Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan_

2_Department of Cell Biology and Physiology, University of North Carolina School of Medicine, Chapel Hill, NC_

3_Institute of Innovative Science and Technology, Tokai University, Kanagawa, Japan_

4_Gastroenterology, Jikei University Graduate School of Medicine, Tokyo, Japan_

5_Division of Stem Cell Therapy, Center for Stem Cell and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan_

6_Department of Cancer Biology, Wake Forest School of Medicine, Winston Salem, NC_

7_Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD_

8_Program in Molecular Biology and Biotechnology, University of North Carolina School of Medicine, Chapel Hill, NC_

9_Full member, UNC Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC_

*Institute of Innovative Science and Technology, Tokai University, 143 Shiomokasuya, Isehara, Kanagawa 259-1193, Japan

**Department of Cell Biology and Physiology and Program in Molecular Biology and Biotechnology. Full Member of the Lineberger Cancer Center, UNC School of Medicine, Chapel Hill, NC 27599

corr3_Division of Stem Cell Therapy, Center for Stem Cell and Regenerative Medicine, The Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan_

Email:[email protected]

Received 3 April 2012; Accepted 29 October 2012

View this article online atwileyonlinelibrary.com.

Grant sponsor: Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology in Japan; Grant Numbers: 22790674 23689040; Grant sponsor: Vertex Pharmaceuticals (Cambridge, MA); Grant sponsor: Vesta Therapeutics (Bethesda, MD); Grant sponsor: NCI; Grant Number: CA016086; Grant sponsor: National Cancer Institute; Grant Number: Z01 BC 010876; Grant sponsor: American Cancer Society; Grant Number: RSG-12198-01-TBG.

Potential conflict of interest: Nothing to report.

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Abstract

Liver cancers, including hepatocellular carcinomas (HCCs), cholangiocarcinomas (CCs), and fibrolamellar HCCs (FL-HCCs) are among the most common cancers worldwide and are associated with a poor prognosis. Investigations of genes important in liver cancers have focused on Sal-like protein 4 (SALL4), a member of a family of zinc finger transcription factors. It is a regulator of embryogenesis, organogenesis, pluripotency, can elicit reprogramming of somatic cells, and is a marker of stem cells. We found it expressed in normal murine hepatoblasts, normal human hepatic stem cells, hepatoblasts and biliary tree stem cells, but not in mature parenchymal cells of liver or biliary tree. It was strongly expressed in surgical specimens of human HCCs, CCs, a combined hepatocellular and cholangiocarcinoma, a FL-HCC, and in derivative, transplantable tumor lines in immune-compromised hosts. Bioinformatics analyses indicated that elevated expression of SALL4 in tumors is associated with poor survival of HCC patients. Experimental manipulation of SALL4′s expression results in changes in proliferation versus differentiation in human HCC cell lines in vitro and in vivo in immune-compromised hosts. Virus-mediated gene transfer of SALL4 was used for gain- and loss-of-function analyses in the cell lines. Significant growth inhibition in vitro and in vivo , accompanied by an increase in differentiation occurred with down-regulation of SALL4. Overexpression of SALL4 resulted in increased cell proliferation in vitro , correlating with an increase in expression of cytokeratin19 (CK19), epithelial cell adhesion molecules (EpCAM), and adenosine triphosphate (ATP)-binding cassette-G2 (ABCG2). Conclusion: SALL4′s expression is an indicator of stem cells, a prognostic marker in liver cancers, correlates with cell and tumor growth, with resistance to 5-FU, and its suppression results in differentiation and slowed tumor growth. SALL4 is a novel therapeutic target for liver cancers.